EP3300722A1 - Composition contenant du cinéol destinée à l'administration nasale - Google Patents
Composition contenant du cinéol destinée à l'administration nasale Download PDFInfo
- Publication number
- EP3300722A1 EP3300722A1 EP17203038.9A EP17203038A EP3300722A1 EP 3300722 A1 EP3300722 A1 EP 3300722A1 EP 17203038 A EP17203038 A EP 17203038A EP 3300722 A1 EP3300722 A1 EP 3300722A1
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- EP
- European Patent Office
- Prior art keywords
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- cineole
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Classifications
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Definitions
- the present invention relates to the technical (i.e., medical therapeutic) field of treatment of rhinitis.
- the present invention relates to a cineole-containing composition, in particular a cineol-containing pharmaceutical composition which is preferably suitable for topical, especially nasal, preferably intranasal administration, especially for the treatment of rhinitis, and the use of this cineol restroomn composition and an application device containing this cineol Vietnamese composition
- the cineole-containing composition according to the invention is sometimes synonymously also referred to as an inventive combination or inventive drug combination or as an inventive antirhinitis (antirhinitic).
- rhinitis (synonymously sometimes also referred to as nasal catarrh, runny nose or Koryza) is understood as meaning, in particular, an acute or chronic inflammation of the nasal mucous membranes, the rhinitis in particular infectious (eg viral or bacterial), allergic or pseudoallergic origin can be. Most commonly, rhinitis occurs as part of a so-called cold.
- rhinitis In addition to a distinction between acute rhinitis on the one hand and chronic rhinitis on the other hand, different forms of rhinitis, such as the following rhinitis forms: rhinitis acuta, rhinitis atrophicans, allergic rhinitis, hypertrophic rhinitis, rhinitis medicamentosa, pseudomembranacea rhinitis, sicca rhinitis, rhinitis vasomotorica and the environmental rhinitis.
- acute rhinitis rhinitis acuta
- infectious rhinitis which is usually viral, especially by a variety of viruses (especially rhinoviruses and / or adenoviruses), but occasionally can also be triggered bacterially.
- infectious rhinitis which is usually viral, especially by a variety of viruses (especially rhinoviruses and / or adenoviruses), but occasionally can also be triggered bacterially.
- infectious rhinitis which is usually viral, especially by a variety of viruses (especially rhinoviruses and / or adenoviruses), but occasionally can also be triggered bacterially.
- the main feature of an acute rhinitis is a so-called runny nose and a blockage of the nose due to the swelling of the mucous membranes.
- Rhinitis ie inflammation of the nasal mucosa
- acute rhinitis can often also be present simultaneously with an inflammation of the sinus mucosa (sinusitis).
- sinus mucosa sinusitis
- rhinitis For further details on the term rhinitis, reference can be made in particular to Pschyrembel, Medical Dictionary, 257th edition, pages 1331/1332, in particular keywords: " rhinitis “, “ rhinitis allergica “, “ rhinitis atrophicans “, “ rhinitis hyperplastica “, “ rhinitis pseudomembranacea “ , “ rhinitis sicca “and” rhinitis vasomotorica " .
- rhinitis especially acute rhinitis
- intranasal compositions to be applied which so-called sympathomimetics (synonymously also referred to as “subsurface”, “Dekongestiva” or the like), preferably alpha-sympathomimetics (such as xylometazoline and oxymetazoline or their physiological compatible or harmless salts).
- the sympathomimetics have neither antibacterial nor antiviral effects. Some of the sympathomimetics also have serious systemic (eg cardiovascular) side effects, in particular in the case of overdose or in the therapy of certain patients (eg small children, patients with cardiovascular pre-existing conditions, etc.).
- certain sympathomimetic-containing compositions are sometimes incorporated further active substances or ingredients, for example herbal Extracts or herbal ingredients, moisturizing or mucous-caring additives, antihistamines, salts, etc. (cf., for example DE 195 41 919 A1 . DE 195 49 421 A1 and DE 103 56 248 A1 ).
- the problem underlying the present invention therefore consists in the provision of a composition suitable for topical, in particular nasal, preferably intranasal administration, in particular for the treatment of rhinitis, in particular a pharmaceutical composition which at least largely avoids the previously described disadvantages of the prior art or but at least weakens.
- such a composition should have an improved efficacy and / or an improved side-effect profile compared to conventional sympathomimetic-containing pharmaceutical preparations intended for the treatment of rhinitis by topical or intranasal administration.
- the present invention proposes, according to a first aspect of the present invention, a cineol-containing composition, in particular a pharmaceutical composition according to claim 1; Further, particularly advantageous embodiments of the composition according to the invention are the subject of the relevant subclaims.
- the present invention relates to an application device containing the cineol-containing composition according to the invention in accordance with the relevant device claim.
- the present invention - according to a further and third aspect of the present invention - relates to the use according to the invention of the cineole-containing composition according to the present invention, as defined in the corresponding use claims.
- the present invention is associated with numerous advantages and particularities, which are discussed below in a non-limiting manner and are to be considered indicative of patentability.
- an effective antirhinitic agent (antirhinitic) which manages without the compelling presence of alpha-sympathomimetics, so that the undesired side effects of alpha-sympathomimetics can be avoided.
- composition of the invention possesses, due to the presence of component (a), d. H. the cineole, in particular in the form of 1,8-cineole, in their intended use not only an antibacterial (ie bactericidal or bacteriostatic), but also - as the Applicant has found completely surprising - also an antiviral (ie virucidal or virustatic ) Effect.
- component (a) d. H. the cineole, in particular in the form of 1,8-cineole, in their intended use not only an antibacterial (ie bactericidal or bacteriostatic), but also - as the Applicant has found completely surprising - also an antiviral (ie virucidal or virustatic ) Effect.
- composition according to the invention has an anti-inflammatory or anti-inflammatory effect and, in addition, acts secretolytically or expectorant.
- the composition of the invention can counteract inflammation of the nasal mucosa (as they always occur in rhinitis) in an efficient manner.
- the composition of the invention causes a good humidification of the nasal mucosa.
- an antirhinitic effect is achieved overall.
- the symptoms of rhinitis are efficiently counteracted, in particular also the so-called fluent rhinorrhea (i.e., the composition or combination according to the invention also has an anti-rhinorrheal active profile or active potential).
- composition of the present invention effectively counteracts nasal obstruction associated with rhinitis.
- the composition of the invention not only acts anti-inflammatory or antiinflammatory, but also has, in particular due to the presence of component (b) also mucosal protective and wound healing promoting effect, so that inflammation of the nasal mucosa, as they always occur in rhinitis acts effectively counteracted.
- the component (b) acts to nourish and moisturize the nasal mucosa, thus counteracting the drying out of the nasal mucosa and barking.
- composition according to the invention due to the antimicrobial, in particular bactericidal or bacteriostatic active potential of cineole, a good stability, in particular storage stability and long-term stability, of the composition according to the invention is achieved.
- additional measures eg pH adjustment or pH control and use of chemical buffer systems, emulsifiers, thickeners, etc.
- the stability of the composition according to the invention can be further improved.
- the active profile and stability behavior of the composition according to the invention can be controlled or specifically adjusted.
- the cineole-containing composition according to the present invention contains as component (a) cineole, preferably 1,8-cineole.
- cineole in particular in the form of 1,8-cineole, belongs to the bicyclic epoxy-monoterpenes, more particularly to limonoxides.
- Synonyms for 1,8-cineole with the chemical formula C 10 H 18 O are eucalyptol, lime-1,8-oxide, 1,8-epoxy-p-menthan or 1,3,3-trimethyl-2-oxabicyclo [ 2.2.2] octane.
- 1,8-cineole comes as a main component of eucalyptus oil (eucalyptus oil contains up to 85 wt .-% 1,8-cineole), but also in other plants, such. In mint, healing sage, thyme, basil and tea tree; In addition, 1,8-cineole is included, for example, in niaouli, juniperus, piper, cannabis, cajeput, sage, myrtle, and other essential oils.
- Technical 1,8-cineol which is generally 99.6% to 99.8%, is generally recovered by fractional distillation of eucalyptus oil.
- the cineole in particular 1,8-cineole, develops in the composition according to the invention, when used as intended, not only an antibacterial (ie bactericidal or bacteriostatic), but also (as the Applicant has surprisingly found) also a antiviral (ie virucidal or virustatic) effect.
- the cineole in particular 1,8-cineole, in the context of the composition according to the invention has an overall anti-inflammatory or antiinflammatory effect and, in addition, secretolytic or expectorant;
- component (b) ie pantothenol or pantothenic acid
- it effectively counteracts inflammation of the nasal mucous membrane and also ensures good moistening of the nasal mucosa.
- an antirhinitic effect is achieved overall and, in addition, the symptoms of rhinitis are efficiently counteracted, in particular so-called coryza (rhinorrhoea) (ie the composition or combination according to the invention also has an antirhinorrheal profile of action or potential for action).
- the cineole in conjunction with component (b), effectively counteracts nasal obstruction associated with rhinitis.
- the cineole is also beneficial in terms of stability, in particular storage stability and long-term stability, of the composition according to the invention.
- component (a) contains the cineole as pure substance, in particular free from other terpenes, preferably with a purity of at least 95% by weight, in particular at least 96% by weight, preferably at least 97% by weight. %, more preferably at least 98 wt .-%, most preferably at least 99 wt .-%, even more preferably at least 99.5%, based on the cineole.
- the composition preferably contains no further terpene besides the cineole.
- the cineole in the cineole-containing composition according to the present invention, is present as a pure substance, i. H. the cineole used in the cineol restroomn composition according to the present invention is free of other terpenes or contains no other terpenes.
- the cineole used as component (a) has a purity of at least 95 wt .-%, in particular at least 96 wt .-%, preferably at least 97 wt .-%, particularly preferably at least 98 wt .-%, most preferably at least 99 wt .-%, more preferably at least 99.5%, based on the cineole, on.
- the composition according to the invention contains cineole as 1,8-cineole or cineole as 1,8-cineole (ie in other words according to this particular embodiment component (a) contains the cineole in the form of 1,8-cineole).
- cineole as a pure substance, in particular in the form of 1,8-cineole, ensures a defined or controllable profile of action. In particular, unwanted or unpredictable changes and side effects are avoided due to the absence of other terpenes.
- the component (a) or the cineol can be present or formulated in liposome-surrounded and / or liposomally packaged form.
- an improved solubility or emulsifiability of the cineol is achieved with simultaneously good stabilization of the cineol in the composition and with good bioavailability.
- the amount of component (a) or cineol in the cineol restroomn composition according to the present invention can be varied within wide ranges.
- the composition of the invention, the component (a) or the cineole, based on the composition in relative amounts in the range of 0.001 to 10 wt .-%, in particular 0.002 to 5 wt .-%, preferably 0 , 01 to 3 wt .-%, preferably 0.05 to 3 wt .-%, particularly preferably 0.1 to 2.5 wt .-%, very particularly preferably 0.2 to 2 wt .-%, even more preferably 0.3 to 1 wt%, most preferably 0.4 to 0.8 wt%.
- component (a) ie cineole, preferably in the form of 1,8-cineol
- component (a) is administered at a single dose in the range from 0.01 mg to 50 mg, in particular in the range of 0.1 mg to 25 mg, preferably in the range of 0.5 mg to 20 mg, preferably in the range of 1 mg to 15 mg, more preferably in the range of 2 mg to 10 mg, is administered or when component (a) is for administration at a single dose in the range of 0.01 mg to 50 mg, in particular in the range of 0.1 mg to 25 mg, preferably in the range of 0.5 mg to 20 mg, preferably in the range from 1 mg to 15 mg, more preferably in the range of 2 mg to 10 mg.
- pantothenol preferably dexpanthenol (D-pantothenol), or its physiologically acceptable esters and / or pantothenic acid or their physiologically acceptable salts (pantothenates)
- D-pantothenol dexpanthenol
- pantothenic acid or their physiologically acceptable salts pantothenates
- pantothenol preferably dexpanthenol (D-pantothenol), or its physiologically acceptable esters and / or pantothenic acid or its physiologically acceptable salts.
- the active ingredient pantothenol is chemically polyols and amides and is physiologically a provitamin (i.e., a precursor of a vitamin of the vitamin B group) which is converted in the body to pantothenic acid (vitamin B5).
- the active ingredient pantothenic acid in turn is a component of coenzyme A and thus plays an essential role in (mucus) skin metabolism.
- component (b) ie pantothenol, preferably dexpanthenol, or its physiologically acceptable ester or pantothenic acid or its physiologically acceptable salts
- component (b) does not only exert a mucosal protective and wound healing promoting effect but also acts also independently anti-inflammatory or anti-inflammatory.
- the cineole especially 1,8-cineole, therefore, inflammation of the nasal mucosa, as they always occur in rhinitis, counteracted efficiently.
- component (b) acts to nourish and moisturize the nasal mucosa, so that in this way a good moistening of the nasal mucosa is effected or a desiccation of the nasal mucous membrane and a bark formation is counteracted.
- component (b), in cooperation with component (a) achieves improved nasal breathing.
- an antirhinitic effect is achieved as a whole and, in addition, the symptoms of rhinitis are efficiently counteracted, in particular also coryza (rhinorrhoea) (ie, the composition or combination according to the invention also has an antirhinorrheal profile of action, as stated above or active potential).
- the composition contains, as component (b), pantothenol, preferably dexpanthenol (D-pantothenol), or its physiologically acceptable ester
- composition as component (b) it is particularly preferred for the composition as component (b) to contain pantothenol, preferably in the form of dexpanthenol (D-pantothenol).
- the amount of component (b) in the cineole-containing composition of the present invention can be varied widely.
- the composition according to the invention contains component (b), relative to the composition, in relative amounts in the range from 0.01 to 10% by weight, in particular from 0.1 to 8% by weight, preferably 0 From 5 to 7% by weight, preferably from 1 to 6.5% by weight, more preferably from 2 to 6% by weight, very preferably from 4 to 6% by weight, even more preferably from 4.5 to 5, 5 wt .-%, contains.
- component (b) relative to the composition, in relative amounts in the range from 0.01 to 10% by weight, in particular from 0.1 to 8% by weight, preferably 0 From 5 to 7% by weight, preferably from 1 to 6.5% by weight, more preferably from 2 to 6% by weight, very preferably from 4 to 6% by weight, even more preferably from 4.5 to 5, 5 wt .-%, contains.
- component (b) ie pantothenol or pantothenic acid
- component (b) ie pantothenol or pantothenic acid
- component (b) preferably in the form of pantothenol, particularly preferably dexpanthenol
- component (b) for administration at a single dose in the range of 0.1 mg to 50 mg, in particular in the range of 0.5 mg to 25 mg, preferably in the range of 1 mg to 20 mg, preferably in the range of 2.5 mg to 10 mg, more preferably in the range of 4 mg to 8 mg
- component (b) preferably in the form of pantothenol, more preferably dexpanthenol
- the composition according to the invention comprises components (a) and (b) in a ratio of component (a) to component (b) in the range from 1: 1 to 1: 500, in particular 1: 1.25 to 1: 100, preferably 1: 1.5 to 1: 75, preferably 1: 2 to 1: 50, more preferably 1: 2.5 to 1: 25, most preferably 1: 2.75 to 1: 20, more preferably 1: 3 to 1:10. Nevertheless, it may be necessary, on a case-by-case or application basis, to deviate from the abovementioned values without departing from the scope of the present invention (which is at the discretion of the person skilled in the art).
- composition according to the present invention also contains as component (c) at least one emulsifier.
- An emulsifier in the context of the present invention is a formulation adjuvant which serves to mix and stabilize two substances which are not or only slightly miscible with one another to form a finely divided mixture (that is to say emulsion).
- emulsion a finely divided mixture
- component (a) d. H. of the cineole, but optionally also of component (b), with or in the aqueous excipient (carrier) of the composition according to the invention and stabilizing the resulting emulsion.
- an emulsifier with respect to the composition according to the invention is optional, but represents a preferred embodiment for the aforementioned reasons.
- the amount of component (c) or emulsifier in the cineol restroomn composition according to the present invention can be varied within a wide range or adjusted.
- the composition according to the invention contains component (c) and / or the emulsifier, based on the composition, in relative amounts in the range from 0.0001 to 10% by weight, in particular from 0.001 to 5% by weight. , preferably 0.005 to 4 wt .-%, preferably 0.01 to 3 wt .-%, particularly preferably 0.05 to 2.5 wt .-%, most preferably 0.1 to 2 wt .-%, even more preferably 0.2 to 1.8% by weight, most preferably 0.5 to 1.5% by weight.
- component (c) or the emulsifier can in principle be selected from a multiplicity of very different compounds.
- component (c) or the emulsifier is selected from the group of (i) fatty acids, fatty acid salts, fatty acid amides and fatty acid esters, in particular fatty acid esters, (ii) optionally (poly) ethoxylated and / or hydrogenated (ie partially or completely hydrogenated) castor oils, (iii) organic carboxylic acids and their salts and esters, especially citric acid and its salts (citrates), (iv) organic betaines, (v) organic ammonium compounds, (vi) physiological (ii) phospholipids, in particular phosphatidylcholines and lecithins, (viii) poloxamers (ethylene oxide / propylene oxide block copolymers), (ix) esters of polyhydric alcohols (polyalcohols), in particular glycerol esters
- component (c) or the emulsifier may be selected from the group consisting of (i) fatty acids, fatty acid salts, fatty acid amides and fatty acid esters, especially fatty acid esters, and (ii) optionally (poly) ethoxylated and / or hydrogenated castor oils and theirs combinations.
- composition according to the invention also contains as component (d) at least one chemical buffer system, in particular in the form of buffer salt (s).
- the chemical buffer system in particular in the form of buffer salt (s), is used in particular for stabilizing the composition according to the invention.
- the setting of a constant pH by means of the buffer system surprisingly leads to an undesirable degradation of the active ingredients, in particular components (a) and (b), being effectively counteracted during storage even over a relatively long period of time. In this way, the shelf life of the composition according to the invention is improved.
- the amount of component (d) or chemical buffer system in the cineol restroomn composition according to the present invention can be varied within a wide range or adjusted. It is preferred according to the invention if the composition according to the invention contains component (d) or the chemical buffer system, based on the composition and calculated as the sum of all constituents of the chemical buffer system, in relative amounts in the range from 0.001 to 4% by weight, in particular 0 , 01 to 3 wt .-%, preferably 0.05 to 2 wt .-%, preferably 0.1 to 1.5 wt .-%, particularly preferably 0.2 to 1 wt .-%, contains.
- component (d) or the chemical buffer system is used in particular for adjusting and / or maintaining the pH of the composition according to the invention.
- this leads to the fact that an undesired degradation of the active ingredients, in particular of components (a) and (b), during storage is effectively counteracted over a longer period of time and in this way the shelf life of the composition according to the invention is improved.
- the component (d) or the chemical buffer system as a dihydrogen phosphate / monohydrogen phosphate buffer system (synonymous sometimes synonymous as "H 2 PO 4 - / HPO 4 2- buffer (system)” or “Phosphate buffer (system)”), in particular as a Alkalidihydrogenphosphat / Alkalimonohydrogenphosphat buffer system, is present, preferably with a dihydrogen phosphate / monohydrogen phosphate molar ratio of greater than 5: 1, in particular in the range of 5: 1 to 110: 1, particularly preferably in Range of 6: 1 to 105: 1, most preferably in the range of 7: 1 to 200: 1, even more preferably in the range of 7: 1 to 100: 1.
- the pH of the composition according to the invention can vary within wide ranges. It is preferred according to the invention if the composition according to the invention has a pH in the range from 4.5 to 8.0, in particular in the range from 5.0 to 6.5, preferably in the range from 5.0 to 6.2, preferably in Range of 5.0 to 6.0, more preferably in the range of 5.1 to 6.0, most preferably in the range of 5.2 to 5.9, most preferably in the range of 5.3 to 5, 9, or if the pH of the composition according to the invention in the range of 4.5 to 8.0, in particular in the range of 5.0 to 6.5, preferably in the range of 5.0 to 6.2, preferably in Range of 5.0 to 6.0, more preferably in the range of 5.1 to 6.0, most preferably in the range of 5.2 to 5.9, most preferably in the range of 5.3 to 5, 9, adjusted and / or kept constant (preferably by means of at least one chemical buffer system, in particular as defined above).
- the determination of the pH can be carried out by methods known per se to those skilled in the art.
- composition according to the invention also contains as component (e) at least one preservative and / or disinfectant (antiseptic).
- a preservative and / or disinfectant (antiseptic) in the context of the present invention is a formulation adjuvant which serves to counteract microorganisms and / or to develop antimicrobial or wound-disinfecting action.
- an (excessive) infestation of the inventive Composition with microorganisms and thus an undesirable contamination can be counteracted.
- the stability of the resulting composition according to the invention is improved, in particular also with regard to storage for longer periods.
- the presence of a preservative and / or disinfectant but also supports the anti-inflammatory and antibacterial as antiviral profile of action of cineole in the application of the composition of the invention in the treatment of rhinitis.
- a preservative and / or disinfectant (antiseptic) in relation to the composition according to the invention is optional, but represents a preferred embodiment for the aforementioned reasons.
- the amount of component (s) or preservative and / or disinfectant (antiseptic) in the cineol restroomn composition according to the present invention can be varied within a wide range or adjusted.
- the composition of the invention, the component (s) or the preservative and / or disinfectant (antiseptic), based on the composition in relative amounts in the range of 0.001 to 10 wt .-%, in particular 0.005 to 5 Wt .-%, preferably 0.01 to 2 wt .-%, preferably 0.01 to 1 wt .-%, particularly preferably 0.01 to 0.5 wt .-%, more preferably 0.02 to 0, 1 wt .-%, contains. Nevertheless, it may be necessary on a case-by-case or application-related basis to deviate from the abovementioned values without departing from the scope of the present invention. This is at the discretion of the skilled person.
- the component (s) or the preservative and / or disinfectant (antiseptic) can in principle be selected from a large number of different compounds. According to a preferred embodiment it can be provided that the component (s) or the preservative and / or disinfectant (antiseptic) is selected from the group of (i) alkylbenzyldimethylammonium chlorides, in particular C 8 -C 18 -alkylbenzyldimethylammonium chlorides, and mixtures of various Alkylbenzyldimethylammonium chlorides, preferably benzalkonium chloride, (ii) polyhexanide (iii) sorbic acid and its salts (sorbates), in particular potassium sorbate, (iv) chlorhexidine, (v) para-hydroxybenzoic acid esters and mixtures of different para-hydroxybenzoic acid esters, preferably Nipa esters, and
- Combinations of two or more of the abovementioned compounds preferably from the group consisting of (i) alkylbenzyldimethylammonium chlorides, in particular C 8 -C 18 -alkylbenzyldimethylammonium chlorides, and mixtures of various alkylbenzyldimethylammonium chlorides, preferably benzalkonium chloride, (ii) polyhexanide (iii) sorbic acid and salts thereof (Sorbates), in particular potassium sorbate, as well as combinations of two or more of the aforementioned compounds.
- alkylbenzyldimethylammonium chlorides in particular C 8 -C 18 -alkylbenzyldimethylammonium chlorides
- mixtures of various alkylbenzyldimethylammonium chlorides preferably benzalkonium chloride
- polyhexanide iii) sorbic acid and salts thereof (Sorbates), in particular potassium sorbate, as well as combinations of two or
- the component (e) or the preservative and / or disinfectant (antiseptic) is selected from the group of benzalkonium chloride, polyhexanide and sorbates (eg potassium sorbate) and combinations thereof.
- Benzalkonium chloride ie a mixture of alkylbenzyldimethylammonium chlorides whose alkyl moiety consists of C 8 -C 18 chains is very particularly preferred according to the invention as component (e))
- composition according to the invention also contains as component (f) at least one thickener.
- a thickening agent in the context of the present invention is a formulation adjuvant which serves to increase the viscosity of the composition according to the invention (that is, to make the composition more viscous or less flowable).
- component (f) is intended to ensure that the composition according to the invention adheres to the nasal mucosa for a longer time during its intranasal administration, thereby prolonging the duration of action.
- the so-called bioadhesion is improved in this way.
- the drug release can be controlled specifically. Due to the improved mucoadhesive effect due to the presence of the thickening agent, a longer residence time at the site of action and improved moisturization of the nasal mucosa can be achieved.
- the amount of component (f) or thickener in the cineol restroomn composition according to the present invention can be varied within wide ranges.
- the composition according to the invention contains component (f) or the thickener, based on the composition, in relative amounts in the range from 0.0001 to 10% by weight, in particular 0.001 to 8% by weight, preferably 0.005 to 5 wt .-%, preferably 0.01 to 3 wt .-%, particularly preferably 0.05 to 2 wt .-%, even more preferably 0.1 to 1 wt .-%, contains.
- component (f) or the thickener can in principle be selected from a multiplicity of very different compounds.
- component (f) or the thickener is selected from the group of (i) preferably acid glycosaminoglycans or their physiologically acceptable salts or derivatives, in particular hyaluronic acids or their physiologically acceptable salts (hyaluronates), (ii) polysaccharides and hydrocolloids, in particular carrageenans (iii) celluloses and cellulose derivatives, in particular cellulose esters and cellulose ethers, (iv) alginic acids and their salts (alginates), (v) poly (meth) acrylic acids and poly (meth) acrylates, (vi) polyalkylene glycols, in particular polyethylene glycols, (vii) xanthanes and combinations of two or more of the abovementioned compounds.
- the component (f) or the thickening agent is selected from among those from the group of hyaluronic acids or their physiologically acceptable salts (hyaluronates), carrageenans (carrageenans) and combinations thereof.
- hydroxypropylmethylcellulose in particular also referred to as "HPMC”, “hypromellose”, etc.
- HPMC hydroxypropylmethylcellulose
- HPMC is a mixture of different, partially alkyl-substituted celluloses. It is commercially available in various degrees of polymerization and different degrees of substitution.
- the composition according to the invention also contains as component (g) at least one ectoine or ectoine derivative, in particular a hydroxyectoine, in particular in relative amounts in the range of 0.0001 to 10 wt .-%, in particular 0.001 to 5 wt .-%, preferably 0.01 to 2 wt .-%, based on the composition.
- component (g) at least one ectoine or ectoine derivative, in particular a hydroxyectoine, in particular in relative amounts in the range of 0.0001 to 10 wt .-%, in particular 0.001 to 5 wt .-%, preferably 0.01 to 2 wt .-%, based on the composition.
- the composition according to the invention also contains as component (h) at least one preferably imidazoline-based alpha-sympathomimetic or its physiologically acceptable salts; This is especially the case if, in addition, a decongestive or decongestant action of the composition according to the invention is particularly desired (even if the presence of an alpha-sympathomimetic is basically not necessary for the therapeutic success of the composition according to the invention).
- the preferably imidazoline-based alpha-sympathomimetic may in particular be selected from xylometazoline or oxymetazoline, especially in the form of their physiologically acceptable salts, more preferably in the form of their hydrochloride salts, and more preferably xylometazoline hydrochloride.
- the composition according to the invention may comprise the preferably imidazoline-based alpha-sympathomimetic, relative to the composition, in relative amounts in the range of 0.001 to 2% by weight, in particular 0.005 to 1.5% by weight, preferably 0.01 to 1 , 2 wt .-%, preferably 0.02 to 1.0 wt .-%, particularly preferably 0.03 to 0.5 wt .-%, most preferably 0.04 to 0.2 wt .-%, contain ,
- the inventive composition also contains sodium chloride, in particular in relative amounts in the range of 0.001 to 5 wt .-%, in particular 0.01 to 2 wt .-%, preferably 0.1 to 1 wt. %, based on the composition. This may be the case in particular if additional humidification of the nasal mucosa is intended.
- the cineole-containing composition according to the present invention can in principle be present in a wide variety of forms and / or be configured in a wide variety of formulation forms.
- the composition of the present invention may be present as an aqueous composition.
- the composition according to the present invention can be aqueous-based and / or aqueous-formulated, in particular in the form of an aqueous solution or aqueous solubilization. In this way, good physiological compatibility and good applicability are ensured.
- the cineol-containing composition according to the invention may be present as an aqueous system, in particular as an aqueous single-phase system, preferably as an aqueous solution or aqueous solubilization.
- the composition of the present invention comprises a water-based excipient or carrier.
- the composition according to the invention is present as a clear, colorless aqueous solution. This ensures on the one hand a good physiological compatibility and a good applicability and on the other hand a good stability, in particular storage stability, even over long periods.
- the determination of the appearance of the composition according to the invention can be carried out by methods known to those skilled in the art.
- the determination of the appearance of the composition of the invention according to the method Ph. Eur. [Pharmacopoea Europaea] 7th edition, basic text 2011, sections 2.2.1 and 2.2.2 , respectively.
- the osmolality of the cineole-containing composition of the present invention can vary widely.
- the determination of the osmolality of the composition according to the invention can be carried out by methods known per se to the person skilled in the art.
- the density of the cineole-containing composition of the present invention can vary widely.
- the cineole-containing composition according to the invention at a temperature of 20 ° C and at a pressure of 1013.25 mbar (atmospheric pressure) has a relative density, based on pure water, in the range of 1.001 to 1.2, in particular Range of 1.005 to 1.15, preferably in the range of 1.005 to 1.105, has. Nevertheless, it may be necessary on a case-by-case or application-related basis to deviate from the abovementioned values without departing from the scope of the present invention.
- the determination of the relative density of the composition according to the invention can be carried out by methods known per se to the person skilled in the art.
- the determination of the relative density of the composition of the invention according to the method Ph. Eur. [Pharmacopoea Europaea] 7th edition, basic work 2011, section 2.2.5 , respectively.
- the viscosity of the cineole-containing composition according to the present invention may also be adjusted or selected within wide limits.
- the composition according to the invention at a temperature of 20 ° C, a dynamic viscosity in Range from 1.001 to 2 mPas, in particular 1.01 to 1.9 mPas, preferably 1.05 to 1.8 mPas, particularly preferably 1.1 to 1.5 mPas (wherein the determination of the dynamic viscosity in particular according to the method to
- the composition according to the invention may be at a temperature of 20 ° C a dynamic viscosity of at least 1.5 mPas, in particular in the range of 1.5 to 10 5 mPas, preferably 1.6 to 10 4 mPas, particularly preferably 1.7 to 10 3 mPas, more preferably 2 to 100 mPas have (wherein the determination of the dynamic viscosity in particular according to the method Ph. Eur.
- the refractive index of the cineole-containing composition of the present invention can vary widely.
- the cineole-containing composition of the invention at a temperature of 20 ° C and at a pressure of 1013.25 mbar (atmospheric pressure) has a refractive index in the range of 1.10 to 1.50, in particular in the range of 1.20 to 1.40, preferably in the range of 1.25 to 1.39. Nevertheless, it may be necessary on a case-by-case or application-related basis to deviate from the abovementioned values without departing from the scope of the present invention.
- the refractive index determination of the composition according to the invention can be carried out by methods known per se to the person skilled in the art.
- the refractive index determination of the composition according to the invention according to the method Ph. Eur. [Pharmacopoea Europaea] 7th edition, basic text 2011, section 2.2.6 , respectively.
- the cineole-containing composition according to the present invention has good stability, in particular storage stability and long-term stability.
- the composition is at temperatures in the range of 20 ° C to 50 ° C, at a pressure of 1013.25 mbar (atmospheric pressure) and at a relative humidity in the range of 50% to 90% at least 6 months, in particular at least 12 months, preferably at least 24 months, preferably at least 36 months, stable, in particular storage-stable, formed.
- the cineol-containing composition according to the invention comprises at least one further ingredient, in particular adjuvant and / or additive.
- the further ingredient, in particular excipient and / or additive may in particular be selected from the group of processing aids, stabilizers, emulsifiers, antioxidants, humectants, thickeners, antiseptics, dyes, flavorings, fragrances, fragrances, extenders, binders, wetting agents, vitamins, trace elements , Minerals, micronutrients and / or essential oils and combinations thereof (ie combinations of two or more of the aforementioned ingredients).
- the cineole-containing composition of the present invention has a broad application profile.
- the present invention relates to a cinol-containing composition as described above for use in the prophylactic and / or curative topical treatment of rhinitis, especially rhinitis acuta.
- the present invention - according to a second aspect of the present invention - relates to an application device which contains a cineol-containing composition according to the present invention as described above, wherein the application device according to the invention is particularly suitable and preferred for topical, in particular nasal, preferably intranasal administration in the form of a container with drip or spray.
- the application device according to the invention has a spray device for preferably uniform application of the composition according to the present invention in an amount per spray in the range from 25 ⁇ l to 300 ⁇ l, in particular in the range from 50 ⁇ l to 200 ⁇ l, preferably in the range from 75 ° ⁇ l to 125 ⁇ l.
- the application device in particular to have a container or a storage container with a volume in the range from 5 ml to 100 ml, in particular 10 ml to 50 ml.
- This container or this reservoir then serves to hold the composition of the invention.
- Another object of the present invention - according to a third aspect of the present invention - is the use of a cineol restroomn composition according to the present invention for the prophylactic and / or curative topical treatment of rhinitis of all kinds, especially rhinitis acuta, or the use of a as described above according to the present invention for the manufacture of a medicament for the prophylactic and / or curative topical treatment of rhinitis of all kinds, in particular rhinitis acuta.
- the term of the drug is to be understood very extensively and includes not only drugs or pharmaceuticals as such (ie in terms of drug law), but especially so-called medical devices and above but also homeopathic remedies and dietary supplements as well as cosmetics and utensils.
- the cineol-containing composition according to the invention can thus be present in the form of a pharmaceutical (pharmaceutical), medical device, homeopathic, dietary supplement, cosmetic or everyday object.
- composition of the invention for the treatment of rhinitis of all kinds especially rhinitis acuta , rhinitis allergica , rhinitis atrophicans , rhinitis hyperplastica or hypertrophicans , rhinitis mutilans , rhinitis nervo sa or vasomotorica, environmental rhinitis or rhinitis pseudomem branacea, preferably rhinitis acuta used.
- composition according to the invention as described above, can be applied topically, in particular nasally, preferably intranasally.
- the application device according to the invention as described above can be used.
- a clear aqueous solution of the composition according to the invention To prepare in each case 1,000 g of a clear aqueous solution of the composition according to the invention, the procedure is carried out in a manner known per se. First, a defined amount of purified water is introduced at room temperature and ambient pressure in a corresponding glass vessel with stirring device and subsequently with a solution of the selected buffer system adjusted to a predetermined pH in the range between 5.3 and 5.9 (eg pH of about 5.5) with subsequent control of the achieved pH.
- a predetermined pH in the range between 5.3 and 5.9 eg pH of about 5.5
- the other corresponding specifications of the solution are also checked for the selected or preselected value ranges (eg osmolality, relative density, microbiological purity and sterility, exclusion of impurities, in particular decomposition products of the ingredients and active substances, viscosity, appearance, refractive index).
- a portion of the resulting solution is finally bottled in narrow mouth bottles of brown glass to 10 ml or 20 ml, which can be optionally equipped with a dropper pipette or a Sprühdosierpumpe; for proper use, one to three drops or one to two sprays can be given and raised several times daily in each nostril. Another part of the solution obtained is used for stability studies.
- Buffer system Ph. Eur. Potassium dihydrogen phosphate / 0,008 Sodium monohydrogen phosphate (dodecahydrate) 0,100 sodium chloride 0.900 Ph. Eur. Emulsifier (undecylenamidopropyl betaine) 0,100 Ph. Eur. Purified water 93.292 Ph. Eur. Viscosity (20 ° C): 1.25-1.30 mPas ingredient Amount / weight% quality cineole 0,600 Ph. Eur. dexpanthenol 5,000 Ph. Eur. Buffer system: Ph. Eur. Potassium dihydrogen phosphate / 0,008 Sodium monohydrogen phosphate (dodecahydrate) 0,100 Ectoin 2,000 Ph. Eur.
- Emulsifier (undecylenamidopropyl betaine) 0,100 Ph. Eur. Purified water 92.192 Ph. Eur. Viscosity (20 ° C): 1.35-1.40 mPas ingredient Amount / weight% quality cineole 0,600 Ph. Eur. dexpanthenol 5,000 Ph. Eur. Buffer system: Ph. Eur. Potassium dihydrogen phosphate / 0,008 Sodium monohydrogen phosphate (dodecahydrate) 0,100 Ectoin 2,000 Ph. Eur. Emulsifier (undecylenamidopropyl betaine) 0,100 Ph. Eur. Xylometazolinhydrochlorid 0,100 Ph. Eur. Purified water 92.092 Ph. Eur. Viscosity (20 ° C): 1.38-1.40 mPas
- aqueous compositions according to the present invention are each prepared with 0.600% by weight of 1,8-cineole and 5,000% by weight of dexpanthenol (in each case based on the composition).
- compositions A1 to A6 aqueous compositions
- Compositions A1 to A6 are each prepared with 0.800% by weight of 1,8-cineole and 4.750% by weight of dexpanthenol (in each case based on the composition).
- a pH in the range of 5.3 to 5.9 is respectively set (0.853% by weight of potassium dihydrogen phosphate and 0.027% by weight of sodium monohydrogenphosphate dodecahydrate, in each case based on the composition).
- composition A1 contains no further ingredients than the aforementioned ingredients.
- compositions A2 to A6 are additionally admixed with further ingredients (ie emulsifier [polyethoxylated hydrogenated castor oil] and / or preservative / disinfectant [benzalkonium chloride] and / or thickener [sodium hyaluronate]), as indicated below (US Pat.
- Composition A2 1.250% by weight of emulsifier
- Composition A3 0.050% by weight of preservative / disinfectant
- Composition A4 1.250% by weight of emulsifier and 0.050% by weight of preservative / disinfectant
- Composition A5 1.500% by weight % Thickener
- composition A6 1.250% by weight emulsifier, 0.050% by weight preservative / disinfectant and 1.500% by weight thickener).
- composition Shelf life A1 37.5 months A2 40.5 months A3 39.5 months A4 44.5 months A5 38.5 months A6 45.5 months
- compositions according to the invention As the investigations show, particularly good storage capabilities are obtained if, in addition to the actual active ingredients (cineole and dexpanthenol), further ingredients based on emulsifiers, preservatives / disinfectants and / or thickeners are added to the compositions according to the invention.
- inventive compositions A1 to A6 described in the above embodiment 2 b) are tested for their antibacterial and antiviral activity.
- a further, but not inventive composition A7 is tested, wherein the non-inventive composition A7 of the composition of the invention corresponds to A1, but the cineole is replaced by a corresponding proportion of water.
- the antibacterial activity of the compositions is measured in a plate diffusion test and in a dilution test series of 18 bacterial strains (including Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, Bacillus sp., Citrobacter sp., Escherichia coli, Klebsiella sp., Salmonella sp., And Vibrio cholera) tested (determination of MIC concentrations [M ininimal I nhibitory C oncentrations or minimum inhibitory concentration]).
- compositions A1 to A6 exhibit good antibacterial activity, with the composition A6 showing the best antibacterial activity, followed by the compositions A4, A3, A2, A5 and A1 (in order of antibacterial activity); the non-inventive composition A7 shows substantially no antibacterial activity.
- compositions against IBV I n Stammiettess B ronchitis- V irus, IBV Gray strain
- Vero-E6 African green monkey kidney cells [monkey kidney cells]
- Compositions A1 to A6 according to the invention show good antiviral activity (anti-IBV properties), composition A6 showing the best antiviral activity, followed by compositions A4, A3, A2, A5 and A1 (in the order of antiviral activity) ; the non-inventive composition A7 shows substantially no antiviral activity.
- inventive compositions A1 to A6 described in the above embodiment 2 b) and the non-inventive composition A7 described in the above embodiment 2 c) are tested in clinical applications (randomized double-blind placebo-controlled studies).
- compositions A1 to A7 12 volunteers each of a group of 96 patients at the age of 18 to 77 years (31 male, 58 female) each with acute viral rhinitis ("common cold") are treated with the compositions A1 to A7 for 5 days during the duration of their disease, wherein the compositions A1 to A7 are applied topically several times a day as a spray. Another 12 subjects of the subject collective are treated with a non-inventive composition A8, wherein the non-inventive composition A8 contains no drugs (placebo control).
- Target variables include the assessment of nasal obstruction, rhinorrhoea, flushing of the nasal mucosa, dryness of the nasal mucosa, bark formation, healing and tolerability.
- compositions tested show excellent compatibility.
- the composition A6 gives the best result, followed by the compositions A4, A3, A2, A5 and A1 (in the order of effectiveness or acceleration of the healing process); the non-inventive composition A7 and A8 essentially do not accelerate the healing process.
- compositions A1 to A6 tested according to the present invention show excellent efficacy in the treatment of acute rhinitis.
- composition A6 according to the invention gives the best result, followed by compositions A4, A3, A2, A5 and A1 according to the invention (in order of effectiveness).
- compositions A7 and A8 which are not in accordance with the invention have substantially no activity.
- compositions A9 and A10 are tested in clinical trials (double-blind randomized placebo controlled trials): 11 subjects each from a 22 patient population aged 19 to 79 (10 males, 12 females) each with acute viral rhinitis ("cold sneeze") treated for 5 days with the compositions A9 and A10 during the duration of their disease, wherein the compositions are applied topically several times a day as a spray.
- Target variables include the assessment of nasal obstruction, rhinorrhoea, flushing of the nasal mucosa, dryness of the nasal mucosa, bark formation, healing and tolerability.
- target variable (target parameter) of the nasal obstruction which indicates the decongestive effect
- the composition A9 according to the invention score values of (1.0 ⁇ 0.3) and (0.5 ⁇ 0.2 ) (base value: 3.1 ⁇ 0.6), while in the non-inventive composition A10 despite double amount of decongestant the score values after 3 or 5 days (1.2 ⁇ 0.4) and (0.7 ⁇ 0.3) (underlying: 3.0 ⁇ 0.4).
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- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
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- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Otolaryngology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
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Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102014012040 | 2014-08-18 | ||
DE102014012278 | 2014-08-22 | ||
DE102014013145 | 2014-09-10 | ||
DE102014013189 | 2014-09-11 | ||
DE102014116903.4A DE102014116903A1 (de) | 2014-08-18 | 2014-11-19 | Cineolhaltige Zusammensetzung für die nasale Applikation |
PCT/EP2015/064373 WO2016026600A1 (fr) | 2014-08-18 | 2015-06-25 | Composition contenant du cinéol pour application nasale |
EP15733408.7A EP3182957B1 (fr) | 2014-08-18 | 2015-06-25 | Composition contenant du cinéol pour application nasale |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP15733408.7A Division-Into EP3182957B1 (fr) | 2014-08-18 | 2015-06-25 | Composition contenant du cinéol pour application nasale |
EP15733408.7A Division EP3182957B1 (fr) | 2014-08-18 | 2015-06-25 | Composition contenant du cinéol pour application nasale |
Publications (2)
Publication Number | Publication Date |
---|---|
EP3300722A1 true EP3300722A1 (fr) | 2018-04-04 |
EP3300722B1 EP3300722B1 (fr) | 2020-09-16 |
Family
ID=54067266
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP17203038.9A Active EP3300722B1 (fr) | 2014-08-18 | 2015-06-25 | Composition contenant du cinéol destinée à l'administration nasale |
EP15733408.7A Active EP3182957B1 (fr) | 2014-08-18 | 2015-06-25 | Composition contenant du cinéol pour application nasale |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP15733408.7A Active EP3182957B1 (fr) | 2014-08-18 | 2015-06-25 | Composition contenant du cinéol pour application nasale |
Country Status (12)
Country | Link |
---|---|
US (1) | US20170273935A1 (fr) |
EP (2) | EP3300722B1 (fr) |
JP (1) | JP6469843B2 (fr) |
KR (1) | KR20170036058A (fr) |
BR (1) | BR112017003164A2 (fr) |
CL (1) | CL2017000394A1 (fr) |
DE (2) | DE102014116903A1 (fr) |
EA (1) | EA033510B1 (fr) |
ES (2) | ES2764506T3 (fr) |
MX (1) | MX2017002239A (fr) |
PL (1) | PL3182957T3 (fr) |
WO (1) | WO2016026600A1 (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3552601A1 (fr) * | 2018-04-11 | 2019-10-16 | Karl Bodenschatz | Composition pharmaceutique contenant du dexpanthénol et du polihexanide |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102015113802A1 (de) * | 2015-07-06 | 2017-01-12 | Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh | Zusammensetzung für die Behandlung von Rhinitis |
DE102015115107A1 (de) * | 2015-09-01 | 2017-03-02 | Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh | Cineolhaltige wässrige Zusammensetzung für die nasale Applikation |
DE202015106123U1 (de) * | 2015-10-23 | 2016-10-27 | Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh | Monoterpenhaltige Zusammensetzung zur Behandlung von Erkrankungen der Nase |
ES2972897T3 (es) * | 2017-08-10 | 2024-06-17 | Elixir Ilac Arastirma Ve Gelistirme A S | Composiciones descongestionantes nasales que comprenden mentol, dexpantenol e hialuronato de sodio |
AT16516U1 (de) * | 2019-03-18 | 2019-11-15 | Ulrich Sekotill Mba | Nasenspray |
US20220080020A1 (en) * | 2020-08-22 | 2022-03-17 | Luc Montagnier | Compositions and methods for reducing the transmissivity of illnesses using an oral delivery system |
CN112220102B (zh) * | 2020-09-25 | 2022-12-09 | 山东华熙海御生物医药有限公司 | 一种含透明质酸和依克多因的电子烟液及其制备方法 |
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2014
- 2014-11-19 DE DE102014116903.4A patent/DE102014116903A1/de active Pending
- 2014-11-19 DE DE202014105553.3U patent/DE202014105553U1/de active Active
-
2015
- 2015-06-25 JP JP2017508570A patent/JP6469843B2/ja active Active
- 2015-06-25 KR KR1020177005254A patent/KR20170036058A/ko not_active Application Discontinuation
- 2015-06-25 ES ES15733408T patent/ES2764506T3/es active Active
- 2015-06-25 US US15/504,151 patent/US20170273935A1/en not_active Abandoned
- 2015-06-25 WO PCT/EP2015/064373 patent/WO2016026600A1/fr active Application Filing
- 2015-06-25 ES ES17203038T patent/ES2834985T3/es active Active
- 2015-06-25 PL PL15733408T patent/PL3182957T3/pl unknown
- 2015-06-25 EP EP17203038.9A patent/EP3300722B1/fr active Active
- 2015-06-25 MX MX2017002239A patent/MX2017002239A/es unknown
- 2015-06-25 EP EP15733408.7A patent/EP3182957B1/fr active Active
- 2015-06-25 EA EA201790410A patent/EA033510B1/ru not_active IP Right Cessation
- 2015-06-25 BR BR112017003164A patent/BR112017003164A2/pt not_active Application Discontinuation
-
2017
- 2017-02-16 CL CL2017000394A patent/CL2017000394A1/es unknown
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3552601A1 (fr) * | 2018-04-11 | 2019-10-16 | Karl Bodenschatz | Composition pharmaceutique contenant du dexpanthénol et du polihexanide |
WO2019197199A1 (fr) * | 2018-04-11 | 2019-10-17 | Karl Bodenschatz | Composition pharmaceutique contenant du dexpanthénol et du polihexanide |
Also Published As
Publication number | Publication date |
---|---|
EP3182957A1 (fr) | 2017-06-28 |
US20170273935A1 (en) | 2017-09-28 |
DE202014105553U1 (de) | 2015-08-20 |
JP6469843B2 (ja) | 2019-02-13 |
EP3182957B1 (fr) | 2019-10-16 |
EP3300722B1 (fr) | 2020-09-16 |
EA201790410A1 (ru) | 2017-10-31 |
ES2764506T3 (es) | 2020-06-03 |
BR112017003164A2 (pt) | 2017-11-28 |
DE102014116903A1 (de) | 2016-02-18 |
KR20170036058A (ko) | 2017-03-31 |
EA033510B1 (ru) | 2019-10-31 |
JP2017525701A (ja) | 2017-09-07 |
ES2834985T3 (es) | 2021-06-21 |
MX2017002239A (es) | 2017-05-09 |
CL2017000394A1 (es) | 2017-11-03 |
PL3182957T3 (pl) | 2020-05-18 |
WO2016026600A1 (fr) | 2016-02-25 |
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